Afrin Shumaila, Nguyen Binh An, Singh Virender, Singh Preeti, Bassett Parker, Pekala Maja, Evers Bret, Lopez Christian, Ahmed Yasmin, Li Li, Kallem Raja Reddy, Lemoff Andrew, Argyropoulos Christos, Kluve-Beckerman Barbara, Saelices Lorena
Center for Alzheimer's and Neurodegenerative Diseases, Department of Biophysics, Peter O'Donnell Jr Brain Institute, University of Texas Southwestern Medical Center (UTSW), Dallas, TX, USA.
SciKonnect and BioPatriKa, India.
bioRxiv. 2025 Jul 18:2025.07.15.664973. doi: 10.1101/2025.07.15.664973.
ALECT2 amyloidosis is a rare systemic disease characterized by the pathological deposition of leukocyte cell-derived chemotaxin-2 (LECT2) as amyloid fibrils, primarily affecting the kidneys and liver. The molecular mechanisms underlying LECT2 aggregation remain poorly defined, hindering diagnostic and therapeutic development. Here, we present cryo-electron microscopy structures of ALECT2 fibrils extracted from a patient's kidney. We identified three fibril polymorphs: a predominant single-protofilament morphology and two minor double-protofilament morphologies. The dominant single-protofilament morphology comprises the full-length 133-residue LECT2 protein and retains all three native disulfide bonds. Low-resolution reconstructions of double-protofilament morphologies suggest they adopt a similar fold to the single protofilament morphology, but form paired assemblies with different inter-filament interfaces. Mass spectrometry also reveals acetylation within the fibrils. These findings offer critical insights into the structural basis of ALECT2 amyloid formation and identify molecular features that could inform future diagnostic and therapeutic approaches.
ALECT2淀粉样变性是一种罕见的全身性疾病，其特征是白细胞衍生趋化因子2（LECT2）以淀粉样纤维的形式病理性沉积，主要影响肾脏和肝脏。LECT2聚集的分子机制仍不清楚，这阻碍了诊断和治疗方法的发展。在此，我们展示了从一名患者肾脏中提取的ALECT2纤维的冷冻电子显微镜结构。我们鉴定出三种纤维多晶型：一种主要的单原纤维形态和两种次要的双原纤维形态。占主导地位的单原纤维形态由全长133个残基的LECT2蛋白组成，并保留了所有三个天然二硫键。双原纤维形态的低分辨率重建表明，它们采用与单原纤维形态相似的折叠方式，但形成具有不同丝间界面的配对组装。质谱分析还揭示了纤维内部的乙酰化修饰。这些发现为ALECT2淀粉样蛋白形成的结构基础提供了关键见解，并确定了可为未来诊断和治疗方法提供依据的分子特征。
